Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a β1 integrin viability signaling pathway
Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a β1 integrin viability signaling pathway
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DOI：
10.1074/jbc.m313265200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Henke, CA
中科院分区：
文献类型：
--
作者：
Xia, H;Nho, RS;Henke, CA
β（1）整联蛋白作为一种机械感受器，感受胶原基质收缩过程中产生的机械刺激，并下调磷脂酰肌醇3-激酶（PI 3 K）/Akt存活信号，触发细胞凋亡。粘着斑复合物中负责响应胶原基质收缩传播β 1整合素活力信号的整合素相关信号分子的身份尚不清楚。在这里，我们表明，在响应胶原收缩粘着斑激酶（FAK）是去磷酸化。相反，通过抗β（1）整联蛋白抗体对β（1）整联蛋白的强制活化（其保护成纤维细胞免于凋亡）保留了FAK磷酸化。我们证明，I型胶原连接β（1）整合素或通过抗体强制激活β（1）整合素促进FAK、PI 3 K的p85亚基和Akt的丝氨酸473的磷酸化。渥曼青霉素抑制Akt磷酸化，但不抑制FAK磷酸化，以响应抗体对β（1）整合素的强制激活。通过药物抑制或显性负性FAK阻断FAK可减弱PI 3 K和Akt的p85亚基的磷酸化。显性负性FAK增强胶原收缩过程中的成纤维细胞凋亡，这与Akt活性降低有关。组成性激活的FAK增加PI 3 K的p85亚基和Akt磷酸化水平，并保护成纤维细胞免于凋亡。我们的数据确定了FAK在胶原基质中转导β（1）整联蛋白活力信号中的新作用，FAK在PI 3 K/Akt的上游起作用。
The beta(1) integrin, functioning as a mechanoreceptor, senses a mechanical stimulus generated during collagen matrix contraction and down-regulates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signal triggering apoptosis. The identities of integrin-associated signal molecules in the focal adhesion complex that are responsible for propagating beta1 integrin viability signals in response to collagen matrix contraction are not known. Here we show that in response to collagen contraction focal adhesion kinase (FAK) is dephosphorylated. In contrast, enforced activation of beta(1) integrin by anti-beta(1) integrin antibody, which protects fibroblasts from apoptosis, preserves FAK phosphorylation. We demonstrate that ligation of beta(1) integrin by type I collagen or by enforced activation of beta(1) integrin by antibody promotes phosphorylation of FAK, p85 subunit of PI3K, and serine 473 of Akt. Wortmannin inhibited Akt but not FAK phosphorylation in response to enforced activation of beta(1) integrin by antibody. Blocking FAK by pharmacologic inhibition or by dominant negative FAK attenuated phosphorylation of p85 subunit of PI3K and Akt. Dominant negative FAK augmented fibroblast apoptosis during collagen contraction, and this was associated with diminished Akt activity. Constitutively active FAK augmented levels of p85 subunit of PI3K and Akt phosphorylation, and fibroblasts were protected from apoptosis. Our data identify a novel role for FAK, functioning upstream of PI3K/Akt, in transducing a beta(1) integrin viability signal in collagen matrices.